Biphasic controlled-release formulation and preparation method therefor

Abstract

The present invention relates to a biphasic controlled-release preparation and preparation thereof. The biphasic controlled-release preparation can take effect quickly in vivo, quickly reach a peak value of blood drug concentration, then keep stable release, maintain stable blood drug concentration and reduce the fluctuation between wave peaks and wave valleys. The controlled-release preparation consists of three parts, namely an immediate-release layer, a tablet core layer and a blocking layer. The immediate-release layer is rapidly dissolved in vitro, and the combination of the remaining tablet core layer and the blocking layer can maintain the zero-order release in vitro.

We claim: 
     
         1 . A biphasic controlled-release preparation, which comprises or consists essentially of or consists of a drug-containing immediate-release layer (IR), a drug-containing sustained-release layer (SR) and a drug-free blocking layer (BL), wherein
 the drug-containing sustained-release layer (SR) is wrapped between the drug-containing immediate-release layer (IR) and the blocking layer (BL); and the drug-containing immediate-release layer (IR) is formed by compressing in a tableting manner and covering the drug-containing sustained-release layer (SR).   
     
     
         2 . The biphasic controlled-release preparation according to  claim 1 , wherein the drug-containing immediate-release layer (IR) comprises or consists essentially of or consists of the following components: an active substance, a filler, an adhesive, a disintegrant, a lubricant and a flow aid. 
     
     
         3 . The biphasic controlled-release preparation according to  claim 1 , wherein the drug-containing sustained-release layer (SR) comprises or consists essentially of or consists of the following components: an active substance, a sustained-release polymer, a filler, an adhesive, a lubricant and a flow aid; and the drug-containing sustained-release layer (SR) and the drug-free blocking layer (BL) constitute a partial coating structure with one side opening, wherein the drug-containing sustained-release layer (SR) serves as a tablet core, and the drug-free blocking layer (BL) functions as a partial coating layer. 
     
     
         4 . The biphasic controlled-release preparation according to  claim 1 , wherein the drug-free blocking layer (BL) comprises or consists essentially of or consists of the following components: a sustained-release polymer, a filler, an adhesive, a lubricant and a flow aid. 
     
     
         5 . The biphasic controlled-release preparation according to any one of  claims 1-4 , wherein
 a ratio of the mass of the drug-containing immediate-release layer (IR) to the mass of the drug-containing sustained-release layer (SR) is 5:1-1.5:1;   a ratio of the mass of the drug-containing immediate-release layer (IR) to the mass of the drug-free blocking layer (BL) is 1:1-0.125:1; and   a ratio of the mass of the drug-containing sustained-release layer (SR) to the mass of the drug-free blocking layer (BL) is 0.2:1-0.05:1.   
     
     
         6 . The biphasic controlled-release preparation according to  claim 5 , wherein the content of a filler in the drug-containing sustained-release layer (SR) is 30-70%, and preferably 50%; and the material of the filler is selected from one or more of lactose, sucrose, calcium sulfate, calcium carbonate and calcium phosphate, and preferably lactose. 
     
     
         7 . The biphasic controlled-release preparation according to  claim 5 , wherein the content of an adhesive in the drug-containing immediate-release layer (IR) is 3-10%, the content of an adhesive in the drug-free blocking layer (BL) is 2-10%, and the adhesive is selected from one or more of HPC, HPMC, povidone and sodium carboxymethyl cellulose; wherein the viscosity of HPC is 75-700 cps, and the viscosity of HPMC is 3-50 cps. 
     
     
         8 . The biphasic controlled-release preparation according to  claim 7 , wherein the content of the adhesive in the drug-containing immediate-release layer (IR) is 5%, and the material is composed of HPMC and HPC in a content ratio of 0-1:1. 
     
     
         9 . The biphasic controlled-release preparation according to  claim 1 , wherein the mass of an active substance in the drug-containing sustained-release layer is greater than that in the drug-containing immediate-release layer, and a ratio of the mass of the active substance in the drug-containing sustained-release layer to the mass of the active substance in the drug-containing immediate-release layer is ≤4; and preferably 4:1-1:1. 
     
     
         10 . The biphasic controlled-release preparation according to any one of  claims 3-9 , wherein a disintegrant in the drug-containing immediate-release layer is selected from one or more of crosslinked sodium carboxymethyl starch, crosslinked sodium carboxymethyl cellulose, crospovidone PVPP and low-substituted hydroxypropyl cellulose L-HPC; and preferably crosslinked sodium carboxymethyl starch or crosslinked sodium carboxymethyl cellulose;
 the lubricants in the drug-containing immediate-release layer (IR), the drug-containing sustained-release layer (SR) and the drug-free blocking layer (BL) are independently selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, hydrogenated castor oil and sodium dodecyl sulfate; and preferably magnesium stearate or stearic acid;   the flow aids in the drug-containing immediate-release layer (IR), the drug-containing sustained-release layer (SR) and the drug-free blocking layer (BL) are independently colloidal silicon dioxide or talcum powder; and preferably colloidal silicon dioxide; and   the sustained-release polymer (skeleton material) in the drug-containing sustained-release layer (SR) and the drug-free blocking layer (BL) is hydroxypropyl methylcellulose.   
     
     
         11 . The biphasic controlled-release preparation according to  claim 10 , wherein the content of the hydroxypropyl methylcellulose in the drug-containing sustained-release layer (SR) is 20.00-60.00%, and preferably 25.00-50.00%; and
 the content of the hydroxypropyl methylcellulose in the drug-free blocking layer (BL) is 20.00-60.00%, and preferably 25.00-50.00%.   
     
     
         12 . The biphasic controlled-release preparation according to  claim 10 , wherein the hydroxypropyl methylcellulose in the sustained-release polymer is selected from one or more of E30LV, E50LV, K100LV, K4M, K15M, K100M and xanthan gum. 
     
     
         13 . The biphasic controlled-release preparation according to any one of  claims 1-12 , wherein in an in vitro dissolution test, at least 85% of active ingredients in the drug-containing immediate-release layer (IR) are dissolved within 45 min, and a trend slope of a dissolution curve of active ingredients in the drug-containing sustained-release layer (SR) within 1-10 hours is between 5.0-5.6, with at least 95% being released within 20 hours. 
     
     
         14 . A method for preparing the biphasic controlled-release preparation according to any one of  claims 1 to 13 , comprising the following steps:
 a. preparing granules of an immediate-release layer according to a formulation for later use;   b. preparing granules of a sustained-release layer according to a formulation for later use;   c. preparing granules of a blocking layer according to a formulation for later use;   d. placing the granules of the sustained-release layer into a punching die of a tablet press, and compressing the granules into a plain tablet core for later use; and   e. placing a formulation amount of the granules of the blocking layer into a punching die of a tablet press, placing a plain tablet core layer in the center of the granules of the blocking layer, and pre-compressing at a pre-compression pressure of 0.1-2 KN, so that the plain tablet core forms the drug-containing sustained-release layer (SR), and the plain tablet core is trapped in the granules of the blocking layer, and all faces except the top face of the plain tablet core are surrounded by the blocking layer, thereby forming a partial coating structure with one side opening; and then placing a formulation amount of the granules of the immediate-release layer into the punching die, and applying a main pressure of 5-35 KN, so that the granules of the immediate-release layer cover and adhere on the opening of the partial coating structure in a compression manner to form the drug-containing immediate-release layer (IR), thereby obtaining a finished tablet.   
     
     
         15 . The method according to  claim 14 , wherein the steps a, b and c are specifically as follows:
 a. weighing the active substance, the filler, the disintegrant and the adhesive material other than HPC in a formulation amount required for preparing the drug-containing immediate-release layer, carrying out wet granulation by addition of purified water or an alcohol solution, sieving wet granules through a 1,000-8,000 μm sieve, drying the wet granules, sieving dry wet granules through a 1,000-8,000 μm sieve, adding a flow aid, premixing, and then adding a lubricant and mixing to prepare granules of the immediate-release layer for later use;   b. weighing the active substance, the sustained-release polymer and the filler in a formulation amount required for preparing the drug-containing sustained-release layer, carrying out wet granulation with purified water or an alcohol solution, sieving wet granules through a 1,000-8,000 μm sieve, drying the wet granules, sieving dry granules through a 1,000-8,000 μm sieve, adding a flow aid, premixing, then adding a lubricant and mixing to prepare granules of the sustained-release layer for later use; and   c. weighing the sustained-release polymer, the filler and the adhesive other than HPC in a formulation amount required for preparing the blocking layer, fully mixing them, carrying out wet granulation by addition of purified water or an alcohol solution, sieving wet granules through a 1,000-8,000 μm sieve, drying the wet granules, sieving dry granules through a 1,000-8,000 μm sieve, adding a flow aid, premixing, then adding a lubricant and mixing to prepare granules of the blocking layer for later use;   wherein in the step e, the pre-compression pressure is 0.1-0.5 KN; and a main pressure is 10-25 KN.   
     
     
         16 . The method according to  claim 15 , wherein when the adhesive materials in the drug-containing immediate-release layer (IR) and the blocking layer comprise HPC, the HPC is added by being dissolved in the purified water or alcohol solution used for the wet granulation.